F Griesinger1, G Curigliano2, M Thomas3, V Subbiah4, C S Baik5, D S W Tan6, D H Lee7, D Misch8, E Garralda9, D-W Kim10, A J van der Wekken11, J F Gainor12, L Paz-Ares13, S V Liu14, G P Kalemkerian15, Y Houvras16, D W Bowles17, A S Mansfield18, J J Lin12, V Smoljanovic19, A Rahman19, S Kong20, A Zalutskaya21, M Louie-Gao21, A L Boral21, J Mazieres22. 1. Pius-Hospital, University of Oldenburg, Oldenburg, Germany. 2. European Institute of Oncology, IRCCS, Milan, Italy; University of Milano, Milan, Italy. 3. Thoracic Oncology, Thoraxklinik, University Heidelberg and Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany. 4. University of Texas MD Anderson Cancer Center, Houston, USA. 5. University of Washington School of Medicine, Seattle, USA. 6. National Cancer Centre Singapore, Singapore. 7. Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. 8. Helios Clinic Emil von Behring, Berlin, Germany. 9. Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. 10. Seoul National University College of Medicine and Seoul National University Hospital, Seoul, Republic of Korea. 11. University of Groningen and University Medical Center Groningen, Groningen, Netherlands. 12. Massachusetts General Hospital, Boston, USA. 13. Hospital Universitario 12 de Octubre, Madrid, Spain. 14. Georgetown University, Washington, DC, USA. 15. University of Michigan, Ann Arbor, USA. 16. Weill Cornell Medical College University, New York, USA. 17. University of Colorado School of Medicine, Aurora, USA. 18. Mayo Clinic, Rochester, USA. 19. F. Hoffmann-La Roche, Ltd, Basel, Switzerland. 20. Genentech Inc., South San Francisco, USA. 21. Blueprint Medicines Corporation, Cambridge, USA. 22. Institut Universitaire du Cancer, Toulouse, France. Electronic address: mazieres.j@chuc-toulouse.fr.
Abstract
BACKGROUND: RET fusions are present in 1%-2% of non-small cell lung cancer (NSCLC). Pralsetinib, a highly potent, oral, central nervous system-penetrant, selective RET inhibitor, previously demonstrated clinical activity in patients with RET fusion-positive NSCLC in the phase I/II ARROW study, including among treatment-naïve patients. We report an updated analysis from the ARROW study. PATIENTS AND METHODS: ARROW is a multi-cohort, open-label, phase I/II study. Eligible patients were ≥18 years of age with locally advanced or metastatic solid tumours and an Eastern Cooperative Oncology Group performance status 0-2 (later 0-1). Patients initiated pralsetinib at the recommended phase II dose of 400 mg once-daily (QD) until disease progression, intolerance, consent withdrawal, or investigator's decision. The co-primary endpoints (phase II) were overall response rate (ORR) by blinded independent central review and safety. RESULTS: Between 17 March 2017 and 06 November 2020 (data cutoff), 281 patients with RET fusion-positive NSCLC were enrolled. The ORR was 72% (54/75; 95% CI, 60-82) for treatment-naïve patients and 59% (80/136; 95% CI, 50-67) for patients with prior platinum-based chemotherapy (enrolment cutoff for efficacy analysis: 22 May 2020); median duration of response was not reached for treatment-naïve patients and 22.3 months for prior platinum-based chemotherapy patients. Tumour shrinkage was observed in all treatment-naïve patients and in 97% of patients with prior platinum-based chemotherapy; median progression-free survival was 13.0 and 16.5 months, respectively. In patients with measurable intracranial metastases, the intracranial response rate was 70% (7/10; 95% CI, 35-93); all had received prior systemic treatment. In treatment-naïve patients with RET fusion-positive NSCLC who initiated pralsetinib by the data cutoff (n = 116), the most common Grade 3-4 treatment-related adverse events (TRAEs) were neutropenia (18%), hypertension (10%), increased blood creatine phosphokinase (9%), and lymphopenia (9%). Overall, 7% (20/281) discontinued due to TRAEs. CONCLUSIONS: Pralsetinib treatment produced robust efficacy and was generally well tolerated in treatment-naïve patients with advanced RET fusion-positive NSCLC. Results from the confirmatory phase III AcceleRET Lung study (NCT04222972) of pralsetinib versus standard of care in the first-line setting are pending.
BACKGROUND: RET fusions are present in 1%-2% of non-small cell lung cancer (NSCLC). Pralsetinib, a highly potent, oral, central nervous system-penetrant, selective RET inhibitor, previously demonstrated clinical activity in patients with RET fusion-positive NSCLC in the phase I/II ARROW study, including among treatment-naïve patients. We report an updated analysis from the ARROW study. PATIENTS AND METHODS: ARROW is a multi-cohort, open-label, phase I/II study. Eligible patients were ≥18 years of age with locally advanced or metastatic solid tumours and an Eastern Cooperative Oncology Group performance status 0-2 (later 0-1). Patients initiated pralsetinib at the recommended phase II dose of 400 mg once-daily (QD) until disease progression, intolerance, consent withdrawal, or investigator's decision. The co-primary endpoints (phase II) were overall response rate (ORR) by blinded independent central review and safety. RESULTS: Between 17 March 2017 and 06 November 2020 (data cutoff), 281 patients with RET fusion-positive NSCLC were enrolled. The ORR was 72% (54/75; 95% CI, 60-82) for treatment-naïve patients and 59% (80/136; 95% CI, 50-67) for patients with prior platinum-based chemotherapy (enrolment cutoff for efficacy analysis: 22 May 2020); median duration of response was not reached for treatment-naïve patients and 22.3 months for prior platinum-based chemotherapy patients. Tumour shrinkage was observed in all treatment-naïve patients and in 97% of patients with prior platinum-based chemotherapy; median progression-free survival was 13.0 and 16.5 months, respectively. In patients with measurable intracranial metastases, the intracranial response rate was 70% (7/10; 95% CI, 35-93); all had received prior systemic treatment. In treatment-naïve patients with RET fusion-positive NSCLC who initiated pralsetinib by the data cutoff (n = 116), the most common Grade 3-4 treatment-related adverse events (TRAEs) were neutropenia (18%), hypertension (10%), increased blood creatine phosphokinase (9%), and lymphopenia (9%). Overall, 7% (20/281) discontinued due to TRAEs. CONCLUSIONS: Pralsetinib treatment produced robust efficacy and was generally well tolerated in treatment-naïve patients with advanced RET fusion-positive NSCLC. Results from the confirmatory phase III AcceleRET Lung study (NCT04222972) of pralsetinib versus standard of care in the first-line setting are pending.